ProMIS has developed a rigorous screening and validation process to select the best products to develop among our emerging portfolio of precision therapeutics for Alzheimer’s and ALS. As shown in the figure below, the process starts with identifying specific targets (epitopes) on the prion forms of misfolded proteins, known to play a causative role in the development and progression of AD and ALS. ProMIS uses its proprietary technologies, ProMISTM and Collective Coordinates, to identify these targets. Specific murine monoclonal antibodies (mabs) are raised against these targets and evaluated in a 3-step process, to identify the best products to take into clinical development.
Initial Screening for Binding. This phase allows to identify mabs that bind uniquely and specifically to the prion strains of the misfolded proteins driving AD (Amyloid beta and Tau proteins) and ALS (SOD1 and TDP43 proteins). The top candidate products, showing selective binding to the prion forms and no binding to the non toxic forms, are selected for the validation phase in human tissue
Functional Assays & final product selection. Two complementary assays are used to identify, among the validated product candidates, those that demonstrate blocking of neurotoxicity (blocking the killing of neurons, a hallmark of disease) and inhibition of propagation (spreading throughout the brain) of the prion-like strains of misfolded protein (also a hallmark of disease). Validated product candidates meeting these criteria will undergo final testing to confirm that they block neurotoxicity in an acute animal model.
The neuroprotective effect of product candidates for AD is investigated in a in a memory-behavior test called novel object recognition. Injection of prion-like forms of Amyloid beta (also called toxic soluble oligomers) into the brain of mice causes a neurological deficit that can be assessed. Normal mice exposed to an object remember the familiar object when re-exposed to it and spend more time exploring a newly introduced object. In contrast, mice injected with toxic Amyloid beta oligomers lose the ability to discriminate between known and novel objects and spend equivalent amounts of time exploring both.
Validated product candidates that successfully prevent the cognitive decline (loss of short-term memory formation) caused by toxic oligomers in this setting have now passed through the final hurdle for selection as “lead products for development”. Two ProMIS mAb products, PMN310 and PMN350, each addressing a different target on toxic forms of Amyloid beta, have to date successfully reached this milestone, and have been designated lead AD products for development.
Alzheimer’s Products. ProMIS has identified multiple product candidates against five unique targets on misfolded strains of Aβ that have successfully passed the screening phase. Among these, five lead antibodies, along with several backup candidates, have been confirmed with the ideal target binding profile in brain tissue and CSF from AD patients. In addition, ProMIS is currently raising mab product candidates against a sixth unique misfolded Aβ target. Finally, ProMIS is in the process of initiating identification of unique targets on toxic strains of Tau protein.
ALS Products. ProMIS ALS portfolio consists of three anti-SOD1 mab products that are fully validated and confirmed in multiple functional assays, showing blocking of both the neurotoxicity and the propagation of prion-like strains of misfolded SOD1 in familial and sporadic ALS. In addition, ProMIS is initiating the process to identify unique targets on toxic, misfolded strains of TDP43.
Harnessing the power of precision medicine to conquer Alzheimer’s disease.